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The first patients described with RTH had a very specific phenotype consisting of short stature,
delayed bone maturation and stippled major ossification centers, deaf-mutism and very obvious
winged scapulae (Refetoff, 1967). Further research has shown however that a wide variety of
symptoms exists in this patient group (Table 1) (Beck-Peccoz and Chatterjee, 1994). Up until now
about 600 cases have been described (Weiss 1999a) and the prevalence of the syndrome is estimated
at about 1 in 50.000 (Snyder, 1997). The clinical presentation is heterogeneous. Some subjects have no or minor symptoms, others have more marked symptoms of a hypo- or hyperthyroid nature, even co-existing within one patient. Depending on the clinical presentation, RTH has in the past been divided into two classes. Patients who are able to maintain peripheral euthyroidism by increasing the T4 production which compensates for the decreased tissue sensitivity or who present with hypothyroid symptoms were classified as generalised resistance (GRTH). Those patients who presented with hyperthyroid symptoms were classified as having pituitary resistance (PRTH). Unfortunately the distinction is not as clear cut as it may appear at first glance and has no firm pathophysiological basis. Hyperthyroid symptoms have also been found in patients defined as having GRTH; furthermore no significant differences between GRTH and PRTH exist when parameters like age, sex, goiter frequency, and FT3, FT4 and TSH levels are compared. About two-thirds of the cases patients present with a goitre (Table 1). When the goitre is combined with resting tachycardia, palpitations and high T4 serum concentrations often the wrong diagnosis of Graves' hyperthyroidism has been made (Bantle, 1982). This is now less of a risk since the advent of sensitive TSH assays. It has been shown that the bioactivity of serum TSH in RTH patients is higher then normal even though the immunoreactive TSH is normal, stimulating thyroid growth and T4 and T3 secretion (Persani, 1994). Table 1: Features of RTH
Normal indicates the normal range observed in the general population. RTH, values as found in RTH patients. Non-RTH, values as found in non-affected relatives of RTH patients. (adapted from Brucker-Davis, 1995, and Weiss and Refetoff, 2000) In children attention-deficit hyperactivity disorder (ADHD) has been found more often (75%) in RTH patients then in their unaffected relatives (15%). Furthermore in RTH children problems occur in the areas of reading skills and articulation (Brucker-Davis, 1995). One third of RTH patients has an IQ<85 which could manifest as learning disability, and it has been shown in one family that RTH cosegregates with a lower IQ. The relation to ADHD should not be overinterpreted since a study has shown that in a cohort of children with ADHD no biochemical evidence was found for any RTH patient among them. Other features that have been reported include reduced intrauterine growth, low body mass index (30% of cases), childhood short stature and delayed bone age (Brucker- Davis, 1995). Final adult height is often not affected. No effects of RTH have been found on pubertal development, fertility and life expectancy. In adults, bone mineral density is decreased especially in the femoral neck (mean Z score -0.41). Furthermore recurrent pulmonary and upper respiratory tract infections have been reported, as well as hearing defects which may be the result of recurrent ear infections during childhood (Brucker- Davis, 1995). Atrial fibrillation is often found in older patients. |
